I. Restanosis and Cardiovascular Disease
Stenosis denotes a narrowing or constriction of a duct or canal. A variety of disease processes, such as atherosclerotic lesions, immunological reactions, congenital deformities, etc., can lead to the stenosis of coronary arteries and thus to myocardial ischemia. Percutaneous transluninal coronary angioplasty (PTCA), the insertion and partial inflation of a balloon catheter into a stenotic vessel to effect its repair, has been extensively used to treat stenosis. In 1990, over 300,000 procedures were performed in the United States alone.
The major limitation of PTCA is restenosis (i.e. the re-constriction) of the vascular lesion (Liu, M. W. et al., Circulation 79:1374-1386 (1989), herein incorporated by reference). Restenosis has been found to occur in 30% to 40% of angioplasty patients within 6 months of the procedure (Califf, R. M. et al., J. Amer Col. Cardiol. 172B-13B (1991), McBride, W. et al., N. Engl. J. Med. 31:1734-1737 (1988)). Restenosis develops so rapidly that it may be considered a form of accelerated atherosclerosis induced by injury. The significance of the high restenosis, rate is compounded by the present inability to predict with a high degree of certainty which patients, vessels, or lesions will undergo restenosis. Indeed, arteries that are widely patent 2 days after PTCA, free of obstructive thrombus, have exhibited restenosis at catheterization 4-6 months later (Liu, M. W. et al., Circulation 79:1374-1386 (1989)).
The mechanism of restenosis is thus not fully understood. The angioplasty procedure causes unavoidable injury to arterial walls. Animal studies of atherosclerosis have suggested that after such balloon injury, denudation of endothelial cells occurs, followed by platelet adhesion and aggregation, and by the release of platelet-derived growth factor (PDGF) as well as other growth factors. The basic biologic factors believed to be involved in the occurrence of restenosis include: the extent of injury, platelets, inflammatory cells, growth factors, cytokines, endothelial cells, smooth muscle cells, and extracellular matrix production.
Both early platelet aggregation and thrombus formation, as well as late myointimal proliferation, are believed to affect the development of the recurrent lesions after PTCA (Liu, M. W. et al., Circulation 79:1374-1386 (1989)). Although such platelet-thrombus accumulation appears to be a contributing factor in restenosis after balloon dilatation, direct and indirect evidence strongly supports the concept of intimal hyperplasia or proliferation, and migration of vascular smooth muscle cells (VSNC) of medial, or possibly of intimal, origin as the fundamental process of restenosis (see, for review, Liu, M. W. et al., Circulation 79:1374-1386 (1989)). In particular, atherosclerotic coronaries injured by oversized angioplasty balloons, and atherosclerotic coronaries injured by the deployment of intracoronary stents have been found to display vigorous VSMC migration and proliferation (Rodgers, G. P. et al., Circulation 82:560 (1990); Schwartz, R. S. et al., Circulation 82:2190 (1990); Karas, S. P. et al, J. Amer. Col. Cardiol. 20:467 (1992); Johnson, D. E. et al, Circulation 78(suppl.) II1:II-82 (1988), all herein incorporated by reference). There is also a large body of indirect and experimental data. Intimal thickening induced by balloon injury in normal rat arteries reaches its maximum at 2 months, a time course of the intimal growth that approximates that observed in humans after PTCA (Serruys, P. W. et al., Circulation 77:361-371 (1988)). Intimal hyperplasia is also known to be an important component of restenosis in the atherosclerotic rabbit artery. Medial smooth muscle cells are the major cellular component of the arterial wall, and the intimal proliferation of those cells is the only major reparative or reactive response of the arterial wall to mechanical or inflammatory injury.
In their normal quiescent state, smooth muscle cells proliferate at a very low rate (probably less than 0.1% per day), in response to the presence of growth inhibitory factors, such as heparin. In contrast, endothelial cells, macrophages, and platelets are thought to provide the mitogenic stimulus necessary to the growth of medial smooth muscle cells in normal vessels (Liu, N. W. et al., Circulation 79:1374-1386 (1989)). It has been proposed that situations such as vessel damage cause platelets to aggregate on the angioplasty-induced wound surface. These activated platelets release substances that promote local vasoconstriction and thrombus formation and growth factors that activate mesenchymal cells in the vicinity of injured tissue. Within a few hours sonocytes also appear, increasing in number over the first few days. Like platelets, monocytes secrete growth factors capable of initiating and promoting local tissue mesenchymal cell migration. Such activated platelets and cells produce and release a number of growth stimulating factors (such as platelet derived growth factor (PDGF), epidermal growth factors, insulin-like growth factors, transforming growth factors (TGF-.alpha. and TGF-.beta.), PDGF-like molecules, fibroblast growth factors (acidic and basic), interleukin-1 and somatomedin-C, etc.) that are capable of inducing muscle cell proliferation (Liu, M. W. et al., Circulation 79:1374-1386 (1989); Forrester, J. S. et al., J. Amer. Col. Cardiol. 17:758-769 (1991); Stiles, C. D. et al., J. Supramolec. Struct. 11:489-499 (1980)). In this manner, PDGF and other growth factors are released from platelets and other cells to assist in the repair process.
Studies examining the proliferative activity of smooth muscle cells have found that most enter the growth cycle between 2 and 3 days after balloon injury and the vast majority of proliferation is completed within 7 days Clowes, A. W. et al., Circ. Res. 56:139-145 (1985)). In addition, the population of nondividing smooth muscle cells remains relatively constant between 7 and 14 days, suggesting that if smooth muscle cells proliferate, they do so soon after injury. Smooth muscle cell proliferation thus appears to be an acute response related to the initial injury.